The broad objective of the proposed project is to pivotally advance the analytical power of tandem mass spectrometers used in biomedical research generally and in proteomics particularly. Performing multiple stages of mass spectrometric analysis in tandem has become indispensable both for unraveling the complex structures of proteins and identifying large numbers of proteins. A tandem mass spectrometer probes incisively into the complexities of a molecule's structure by partially breaking it into fragments. In proteomic applications, this is done by exploiting one of a number of physicochemical processes among which are collision-induced dissociation (CID), infrared multiphoton dissociation (IRMPD), electron capture dissociation (ECD), electron detachment dissociation (EDD), electron transfer dissociation (ETD), and electron impact excitation of ions from organics (EIEIO). These processes take place inside the instrument in a cell whose operation relies strictly on electric forces that rapidly change direction. This reliance on devices that depend solely on electric forces (to the exclusion of magnetic forces) needlessly restricts the design, fabrication, and application of tandem mass spectrometers. The applicants have taken advantage of modern magnetic materials to create an electromagnetostatic (EMS) cell that can be installed in any type of tandem mass spectrometer and used to perform all of the aforementioned dissociation processes. Specifically, the applicants submit that a universal EMS tandem- mass-spectrometric dissociation-cell can be built in which it is possible to conduct CID, IRMPD, ECD, EDD, ETD, and EIEIO individually or in various combinations at analytically practical levels. This hypothesis would be tested by 1) elucidating the action of EMS optics on low-energy electrons and ions of both polarities, and 2) quantifying the analytical utility of EMS charged-particle optics in tandem mass spectrometric analyses of peptides and proteins. To meet these two aims, the applicants would design a series of EMS cells using computer modeling, fabricate prototypes based on those designs, mount the prototypes in a high-performance tandem mass spectrometer, and conduct performance-trials on authentic peptides, authentic proteins, and protein-systems with biomedical import. Meeting this project's aims would usher in a transformative mass spectrometric technology. EMS dissociation cells would be simpler to implement, require less maintenance, be simpler to operate, and perform more robustly and productively than dissociation cells based on rapidly oscillating electric forces. From a manufacturing point of view, EMS technology would stimulate development of new instrumentation, software, and methodology; from a research point of view, it would inspire the design of new experiments in biomedical and clinical research, facilitate their execution, and increase their informational output. PUBLIC HEALTH RELEVANCE: Achieving the objectives of this project would usher in a transformative mass spectrometric technology. From a manufacturing point of view, this new technology would stimulate development of new instrumentation, software, and methodology for analyzing proteins and other molecules of biomedical import; from a research point of view, it would inspire the design of new experiments, facilitate their execution, and increase their informational output. Simply put, scientists would be able to exploit more fully the analytical power of mass spectrometry in biomedical and clinical research.